Disease relevance of RAB40B

• The PLZF-RAR alpha fusion protein contains an approximately 120-amino-acid N-terminal motif (called the POZ domain), which is also found in a variety of zinc finger proteins and a group of poxvirus proteins and which mediates protein-protein interactions [1].
• In the HepG2 human hepatoblastoma cell line, both at-RA and 9-cis RA as well as the retinoid X receptor (RXR)-specific agonist LGD 1069, but not the RA receptor (RAR) agonist ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-pro penyl]-benzoic acid (TTNPB), induce apo A-II mRNA levels [2].
• We conclude that CD437 can exert its effects in UMSCC22B human human head and neck squamous cell carcinoma cells by at least two mechanisms: RAR-mediated suppression of squamous differentiation and RAR-independent induction of apoptosis [3].
• Our results suggest that in ovarian carcinomas, AHPN/CD437 induced apoptosis is mediated at least in part via an RAR pathway [4].
• We aimed to study the effect of RA on RAR protein levels in MCF-7 human breast cancer cells [5].

High impact information on RAB40B

• Treatment with RA would not only relieve this inhibition, but the activated PML-RAR protein may actually promote myelocyte differentiation [6].
• The fusion PLZF-RAR alpha gene found in this case, was not found in DNA obtained from the bone marrow of normals, APL with t(15;17) and in one patient with AML-M2 with a t(11;17) [7].
• These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR alpha fusion proteins in the molecular pathogenesis of APL [8].
• The hormone binding ability of the RAR alpha protein was assayed by a charcoal absorption assay and the RAR protein was found to bind to retinoic acid with a Kd of 2.1 x 10(-10) M [9].
• In one case with a normal karyotype, FISH analysis revealed insertion of RAR alpha into 11q23, and PLZF-RAR alpha was the sole fusion gene formed [10].

Biological context of RAB40B

• Because patients with APL can be induced into remission with high dose RA therapy, we propose that the nonliganded PML-RAR protein is a new class of dominant negative oncogene product [6].
• Two NPM-RAR molecules are expressed as a result of alternative RNA splicing [11].
• The NPM-RAR fusion proteins bind to retinoic acid response element sequences as either homodimers or as heterodimers with RXR [11].
• All six patients had PLZF-RAR alpha gene fusion as detected by reverse transcription/polymerase chain reaction assay, Southern blotting, or pulsed-field gel electrophoresis [12].
• Both RAR ligands, however, produced very similar effects on gene expression in MCF-7 cells, suggesting that RARE-dependent transcription is only a minor component of retinoid-induced changes in gene expression [13].

Anatomical context of RAB40B

• The resulting PML-RAR protein induces a block in the differentiation of the myeloid progenitor cells, which can be released by retinoic acid (RA) in vitro and in vivo [14].
• In the common chordate ancestor, RAR came to control the spatial expression pattern of Hox genes in the ectoderm and endoderm along the antero-posterior axis [15].
• Lung sensory receptors with afferent fibers coursing in the vagus nerves are broadly divided into three groups: slowly (SAR) and rapidly (RAR) adapting stretch receptors and bronchopulmonary C fibers [16].
• The cytoplasmic tau was associated with microtubules, but the nucleic tau was observed to form clusters and was associated with RA receptor (RAR) [17].
• A discrete and novel region of the posterior arcuate nucleus, the dorsal medial posterior arcuate nucleus (dmpARC) has been identified, where a battery of gene expression changes for signalling molecules (vgf and histamine H3 receptor) and transcription factors (RXRgamma and RAR) occur in association with seasonal changes in body weight [18].

Associations of RAB40B with chemical compounds

• These data indicate that the NPM-RAR fusion proteins can modulate expression of retinoid-responsive genes in a positive or negative manner, depending on context of the promoter, and lend support to the hypothesis that aberrant transcriptional activation underlies the APL phenotype [11].
• Another model demonstrates in vivo effects of pregnant rat mother's ethanol consumption on retinol, retinyl ester, RA content, RA receptor (RAR) binding, and the levels of RAR expression in developing fetal organs [19].

Other interactions of RAB40B

• The remaining 12-14% of RAR protein was RAR-alpha [20].
• RAR-gamma was the most abundant, representing 87% of RAR protein [20].

Analytical, diagnostic and therapeutic context of RAB40B

• Genome-scale microarray analysis of gene expression was used to compare the effects of two pan-RAR ligands, one of which is a strong agonist of RARE-dependent transcription, whereas the other induces such transcription only weakly and antagonizes the inducing effect of RAR agonists [13].
• Finally, we demonstrated that this putative motif directly interacts with RAR protein in a sequence-specific manner by means of an electrophoretic mobility shift assay [21].
• A case of acute promyelocytic leukemia (APL) with cryptic PML-RAR alpha fusion on 17q and add(15p) as a secondary abnormality was characterized using molecular cytogenetic techniques [22].

References